EP0367566A1 - Interleukin-4-Rezeptoren - Google Patents

Interleukin-4-Rezeptoren Download PDF

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EP0367566A1
EP0367566A1 EP89311244A EP89311244A EP0367566A1 EP 0367566 A1 EP0367566 A1 EP 0367566A1 EP 89311244 A EP89311244 A EP 89311244A EP 89311244 A EP89311244 A EP 89311244A EP 0367566 A1 EP0367566 A1 EP 0367566A1
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receptor
sequence
cells
mammalian
amino acid
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French (fr)
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EP0367566B1 (de
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David J. Cosman
Linda Park
Bruce Mosley
Patricia Beckmann
Carl J. March
Rejean Idzerda
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Immunex Corp
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Immunex Corp
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2866—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against receptors for cytokines, lymphokines, interferons
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/08—Antiallergic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/705—Receptors; Cell surface antigens; Cell surface determinants
    • C07K14/715—Receptors; Cell surface antigens; Cell surface determinants for cytokines; for lymphokines; for interferons
    • C07K14/7155—Receptors; Cell surface antigens; Cell surface determinants for cytokines; for lymphokines; for interferons for interleukins [IL]
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/68—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids
    • G01N33/6863—Cytokines, i.e. immune system proteins modifying a biological response such as cell growth proliferation or differentiation, e.g. TNF, CNF, GM-CSF, lymphotoxin, MIF or their receptors
    • G01N33/6869—Interleukin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Definitions

  • the present invention relates generally to cytokine receptors and, more specifically, to Interleukin-4 receptors.
  • Interleukin-4 also known as B cell stimulating factor, or BSF-1
  • BSF-1 B cell stimulating factor 1
  • BSF-1 B cell stimulating factor 1
  • IL-4 was originally characterized by its ability to stimulate the proliferation of B cells in response to low concentrations of antibodies directed to surface immunoglobulin. More recently, IL-4 has been shown to possess a far broader spectrum of biological activities, including growth co-stimulation of T cells, mast cells, granulocytes, megakaryocytes, and erythrocytes.
  • IL-4 stimulates the proliferation of several IL-2- and IL-3-dependent cell lines, induces the expression of class II major histocompatibility complex molecules on resting B cells, and enhances the secretion of IgE and IgG1 isotypes by stimulated B cells.
  • Both murine and human IL-4 have been definitively characterized by recombinant DNA technology and by purification to homogeneity of the natural murine protein (Yokota et al., Proc. Natl. Acad. Sci. USA 83 :5894,1986; Noma et al., Nature 319 :640,1986; and Grabstein et al., J. Exp. Med. 163 :1405, 1986).
  • IL-4 The biological activities of IL-4 are mediated by specific cell surface receptors for IL-4 which are expressed on primary cells and in vitro cell lines of mammalian origin. IL-4 binds to the receptor, which then transduces a biological signal to various immune effector cells.
  • Purified IL-4 receptor (IL-4R) compositions will therefore be useful in diagnostic assays for IL-4 or IL-4 receptor, and in raising antibodies to IL-4 receptor for use in diagnosis or therapy.
  • purified IL-4 receptor compositions may be used directly in therapy to bind or scavenge IL-4, providing a means for regulating the biological activities of this cytokine.
  • IL-4 has been extensively characterized, little progress has been made in characterizing its receptor. Numerous studies documenting the existence of an IL-4 receptor on a wide range of cell types have been published; however, structural characterization has been limited to estimates of the molecular weight of the protein as determined by SDS-PAGE analysis of covalent complexes formed by chemical cross-linking between the receptor and radiolabeled IL-4 molecules. Ohara et al. ( Nature 325 :537, 1987) and Park et al. ( Proc. Natl. Acad. Sci.
  • human IL-4 receptor is present not only on cell lines of B, T, and hematopoietic cell lineages, but is also found on human fibroblasts and cells of epithelial and endothelial origin.
  • IL-4 receptors have since been shown to be present on other cell lines, including CBA/N splenic B cells (Nakajima et al., J. Immunol. 139 :774, 1987), Burkitt lymphoma Jijoye cells (Cabrillat et al., Biochem. & Biophys. Res. Commun.
  • the present invention provides DNA sequences encoding mammalian Interleukin-4 receptors (IL-4R) or subunits thereof.
  • DNA sequences are selected from the group consisting of: (a) cDNA clones having a nucleotide sequence derived from the coding region of a native IL-4R gene; (b) DNA sequences capable of hybridization to the cDNA clones of (a) under moderately stringent conditions and which encode biologically active IL-4R molecules; and (c) DNA sequences which are degenerate, as a result of the genetic code, to the DNA sequences defined in (a) and (b) and which encode biologically active IL-4R molecules.
  • the present invention also provides recombinant expression vectors comprising the DNA sequences defined above, recombinant IL-4R molecules produced using the recombinant expression vectors, and processes for producing the recombinant IL-4R molecules using the expression vectors.
  • the present invention also provides substantially homogeneous protein compositions comprising mammalian IL-4R.
  • the full length murine molecule is a glycoprotein having a molecular weight of about 130,000 to about 140,000 M r by SDS-PAGE.
  • the apparent binding affinity (K a ) for COS cells transfected with murine IL-4 receptor clones 16 and 18 from the CTLL 19.4 library is 1 to 8 x 109 M ⁇ 1.
  • the K a for COS cells transfected with murine IL-4 receptor clones 7B9-2 and 7B9-4 from the murine 7B9 library is 2 x 109 to 1 x 1010 M ⁇ 1.
  • the mature murine IL-4 receptor molecule has an N-­terminal amino acid sequence as follows: IKVLGEPTCFSDYIRTSTCEW.
  • the human IL-4R molecule is believed to have a molecular weight of between about 110,000 and 150,000 M r and has an N-terminal amino acid sequence, predicted from the cDNA sequence and by analogy to the biochemically determined N-terminal sequence of the mature murine protein, as follows: MKVLQEPTCVSDYMSISTCEW.
  • the present invention also provides compositions for use in therapy, diagnosis, assay of IL-4 receptor, or in raising antibodies to IL-4 receptors, comprising effective quantities of soluble receptor proteins prepared according to the foregoing processes.
  • soluble recombinant receptor molecules include truncated proteins wherein regions of the receptor molecule not required for IL-4 binding have been deleted.
  • IL-4 receptor and "IL-4R” refer to proteins having amino acid sequences which are substantially similar to the native mammalian Interleukin-4 receptor amino acid sequences disclosed in Figures 2 and 4, and which are biologically active as defined below, in that they are capable of binding Interleukin-4 (IL-4) molecules or transducing a biological signal initiated by an IL-4 molecule binding to a cell, or cross-reacting with anti-IL-4R antibodies raised against IL-4R from natural (i.e., nonrecombinant) sources.
  • IL-4 receptor Interleukin-4
  • the native murine IL-4 receptor molecule is thought to have an apparent molecular weight by SDS-PAGE of about 140 kilodaltons (kDa).
  • IL-4 receptor or “IL-4R” include, but are not limited to, analogs or subunits of native proteins having at least 20 amino acids and which exhibit at least some biological activity in common with IL-4R.
  • mature means a protein expressed in a form lacking a leader sequence as may be present in full-length transcripts of a native gene.
  • Various bioequivalent protein and amino acid analogs are described in detail below.
  • substantially similar when used to define either amino acid or nucleic acid sequences, means that a particular subject sequence, for example, a mutant sequence, varies from a reference sequence by one or more substitutions, deletions, or additions, the net effect of which is to retain biological activity of the IL-4R protein.
  • nucleic acid subunits and analogs are "substantially similar" to the specific DNA sequences disclosed herein if: (a) the DNA sequence is derived from the coding region of a native mammalian IL-4R gene; (b) the DNA sequence is capable of hybridization to DNA sequences of (a) under moderately stringent conditions and which encode biologically active IL-4R molecules; or DNA sequences which are degenerate as a result of the genetic code to the DNA sequences defined in (a) or (b) and which encode biologically active IL-4R molecules.
  • Substantially similar analog proteins may be greater than about 30 percent similar to the corresponding sequence of the native IL-4R. Sequences having lesser degrees of similarity but comparable biological activity are considered to be equivalents.
  • the analog proteins will be greater than about 80 percent similar to the corresponding sequence of the native IL-4R, in which case they are defined as being "substantially identical.”
  • all subject nucleic acid sequences capable of encoding substantially similar amino acid sequences are considered substantially similar to a reference nucleic acid sequence. Percent similarity may be determined, for example, by comparing sequence information using the GAP computer program, version 6.0, available from the University of Wisconsin Genetics Computer Group (UWGCG).
  • the GAP program utilizes the alignment method of Needleman and Wunsch ( J. Mol. Biol. 48 :443, 1970), as revised by Smith and Waterman ( Adv. Appl. Math. 2 :482, 1981).
  • the GAP program defines similarity as the number of aligned symbols (i.e., nucleotides or amino acids) which are similar, divided by the total number of symbols in the shorter of the two sequences.
  • the preferred default parameters for the GAP program include: (1) a unary comparison matrix (containing a value of 1 for identities and 0 for non-identities) for nucleotides, and the weighted comparison matrix of Gribskov and Burgess, Nucl. Acids Res. 14 :6745, 1986, as described by Schwartz and Dayhoff, ed., Atlas of Protein Sequence and Structure , National Biomedical Research Foundation, pp. 353-358, 1979; (2) a penalty of 3.0 for each gap and an additional 0.10 penalty for each symbol in each gap; and (3) no penalty for end gaps.
  • Recombinant means that a protein is derived from recombinant (e.g., microbial or mammalian) expression systems.
  • Microbial refers to recombinant proteins made in bacterial or fungal (e.g., yeast) expression systems.
  • recombinant microbial defines a protein produced in a microbial expression system which is essentially free of native endogenous substances. Protein expressed in most bacterial cultures, e.g., E. coli , will be free of glycan. Protein expressed in yeast may have a glycosylation pattern different from that expressed in mammalian cells.
  • Bioly active as used throughout the specification as a characteristic of IL-4 receptors, means that a particular molecule shares sufficient amino acid sequence similarity with the embodiments of the present invention disclosed herein to be capable of binding detectable quantities of IL-4, transmitting an IL-4 stimulus to a cell, for example, as a component of a hybrid receptor construct, or cross-reacting with anti-IL-4R antibodies raised against IL-4R from natural (i.e., nonrecombinant) sources.
  • biologically active IL-4 receptors within the scope of the present invention are capable of binding greater than 0.1 nmoles IL-4 per nmole receptor, and most preferably, greater than 0.5 nmole IL-4 per nmole receptor in standard binding assays (see below).
  • DNA sequence refers to a DNA molecule, in the form of a separate fragment or as a component of a larger DNA construct, which has been derived from DNA isolated at least once in substantially pure form, i.e., free of contaminating endogenous materials and in a quantity or concentration enabling identification, manipulation, and recovery of the sequence and its component nucleotide sequences by standard biochemical methods, for example, using a cloning vector.
  • sequences are preferably provided in the form of an open reading frame uninterrupted by internal nontranslated sequences, or introns, which are typically present in eukaryotic genes. Genomic DNA containing the relevant sequences could also be used. Sequences of non-translated DNA may be present 5′ or 3′ from the open reading frame, where the same do not interfere with manipulation or expression of the coding regions.
  • the sequences are preferably at least 60 bases long.
  • Nucleotide sequence refers to a heteropolymer of deoxyribonucleotides. DNA sequences encoding the proteins provided by this invention can be assembled from cDNA fragments and short oligonucleotide linkers, or from a series of oligonucleotides, to provide a synthetic gene which is capable of being expressed in a recombinant transcriptional unit.
  • Recombinant expression vector refers to a replicable DNA construct used either to amplify or to express DNA which encodes IL-4R and which includes a transcriptional unit comprising an assembly of (1) a genetic element or elements having a regulatory role in gene expression, for example, promoters or enhancers, (2) a structural or coding sequence which is transcribed into mRNA and translated into protein, and (3) appropriate transcription and translation initiation and termination sequences.
  • Structural elements intended for use in yeast expression systems preferably include a leader sequence enabling extracellular secretion of translated protein by a host cell.
  • recombinant protein may include an N-­terminal methionine residue. This residue may optionally be subsequently cleaved from the expressed recombinant protein to provide a final product.
  • Recombinant microbial expression system means a substantially homogeneous monoculture of suitable host microorganisms, for example, bacteria such as E. coli or yeast such as S. cerevisiae , which have stably integrated a recombinant transcriptional unit into chromosomal DNA or carry the recombinant transcriptional unit as a component of a resident plasmid. Generally, cells constituting the system are the progeny of a single ancestral transformant. Recombinant expression systems as defined herein will express heterologous protein upon induction of the regulatory elements linked to the DNA sequence or synthetic gene to be expressed.
  • the present invention provides substantially homogeneous recombinant mammalian IL-4R polypeptides substantially free of contaminating endogenous materials and, optionally, without associated native-pattern glycosylation.
  • the native murine and human IL-4 receptor molecules are recovered from cell lysates as glycoproteins having an apparent molecular weight by SDS-PAGE of about 130-145 kilodaltons (kDa).
  • Mammalian IL-4R of the present invention includes, by way of example, primate, human, murine, canine, feline, bovine, ovine, equine and porcine IL-4R.
  • Derivatives of IL-4R within the scope of the invention also include various structural forms of the primary protein which retain biological activity. Due to the presence of ionizable amino and carboxyl groups, for example, an IL-4R protein may be in the form of acidic or basic salts, or in neutral form. Individual amino acid residues may also be modified by oxidation or reduction.
  • the primary amino acid structure may be modified by forming covalent or aggregative conjugates with other chemical moieties, such as glycosyl groups, lipids, phosphate, acetyl groups and the like, or by creating amino acid sequence mutants.
  • Covalent derivatives are prepared by linking particular functional groups to IL-4R amino acid side chains or at the N- or C-termini.
  • Other derivatives of IL-4R within the scope of this invention include covalent or aggregative conjugates of IL-4R or its fragments with other proteins or polypeptides, such as by synthesis in recombinant culture as N-­terminal or C-terminal fusions.
  • the conjugated peptide may be a signal (or leader) polypeptide sequence at the N-terminal region of the protein which co-translationally or post-­translationally directs transfer of the protein from its site of synthesis to its site of function inside or outside of the cell membrane or wall (e.g., the yeast ⁇ -factor leader).
  • IL-4R protein fusions can comprise peptides added to facilitate purification or identification of IL-4R (e.g., poly-His).
  • the amino acid sequence of IL-4 receptor can also be linked to the peptide Asp-Tyr-Lys-Asp-Asp-Asp-Asp-Lys (DYKDDDDK) (Hopp et al., Bio/Technology 6:1204, 1988.)
  • the latter sequence is highly antigenic and provides an epitope reversibly bound by a specific monoclonal antibody, enabling rapid assay and facile purification of expressed recombinant protein.
  • This sequence is also specifically cleaved by bovine mucosal enterokinase at the residue immediately following the Asp-Lys pairing. Fusion proteins capped with this peptide may also be resistant to intracellular degradation in E. coli.
  • IL-4R derivatives may also be used as immunogens, reagents in receptor-based immunoassays, or as binding agents for affinity purification procedures of IL-4 or other binding ligands.
  • IL-4R derivatives may also be obtained by cross-linking agents, such as M-maleimidobenzoyl succinimide ester and N-hydroxysuccinimide, at cysteine and lysine residues.
  • IL-4R proteins may also be covalently bound through reactive side groups to various insoluble substrates, such as cyanogen bromide-activated, bisoxirane-activated, carbonyldiimidazole-activated or tosyl-activated agarose structures, or by adsorbing to polyolefin surfaces (with or without glutaraldehyde cross-linking).
  • substrates such as cyanogen bromide-activated, bisoxirane-activated, carbonyldiimidazole-activated or tosyl-activated agarose structures, or by adsorbing to polyolefin surfaces (with or without glutaraldehyde cross-linking).
  • IL-4R may be used to selectively bind (for purposes of assay or purification) anti-­IL-4R antibodies or IL-4.
  • the present invention also includes IL-4R with or without associated native-pattern glycosylation.
  • IL-4R expressed in yeast or mammalian expression systems e.g., COS-7 cells, may be similar or significantly different in molecular weight and glycosylation pattern than the native molecules, depending upon the expression system.
  • Expression of IL-4R DNAs in bacteria such as E. coli provides non-glycosylated molecules.
  • Functional mutant analogs of mammalian IL-4R having inactivated N-glycosylation sites can be produced by oligonucleotide synthesis and ligation or by site-­specific mutagenesis techniques. These analog proteins can be produced in a homogeneous, reduced-carbohydrate form in good yield using yeast expression systems.
  • N-glycosylation sites in eukaryotic proteins are characterized by the amino acid triplet Asn-A1-Z, where A1 is any amino acid except Pro, and Z is Ser or Thr.
  • asparagine provides a side chain amino group for covalent attachment of carbohydrate.
  • Such a site can be eliminated by substituting another amino acid for Asn or for residue Z, deleting Asn or Z, or inserting a non-Z amino acid between A1 and Z, or an amino acid other than Asn between Asn and A1.
  • IL-4R derivatives may also be obtained by mutations of IL-4R or its subunits.
  • An IL-4R mutant as referred to herein, is a polypeptide homologous to IL-4R but which has an amino acid sequence different from native IL-4R because of a deletion, insertion or substitution.
  • mammalian IL-4 receptors are presumably encoded by multi-exon genes.
  • Alternative mRNA constructs which can be attributed to different mRNA splicing events following transcription, and which share large regions of identity or similarity with the cDNAs claimed herein, are considered to be within the scope of the present invention.
  • Bioequivalent analogs of IL-4R proteins may be constructed by, for example, making various substitutions of residues or sequences or deleting terminal or internal residues or sequences not needed for biological activity.
  • cysteine residues can be deleted or replaced with other amino acids to prevent formation of incorrect intramolecular disulfide bridges upon renaturation.
  • Other approaches to mutagenesis involve modification of adjacent dibasic amino acid residues to enhance expression in yeast systems in which KEX2 protease activity is present.
  • substitutions should be made conservatively; i.e., the most preferred substitute amino acids are those having physicochemical characteristics resembling those of the residue to be replaced.
  • the potential effect of the deletion or insertion on biological activity should be considered.
  • Subunits of IL-4R may be constructed by deleting terminal or internal residues or sequences. Particularly preferred subunits include those in which the transmembrane region and intracellular domain of IL-4R are deleted or substituted with hydrophilic residues to facilitate secretion of the receptor into the cell culture medium.
  • the resulting protein is a soluble IL-4R molecule which may retain its ability to bind IL-4.
  • Particular examples of soluble IL-4R include polypeptides having substantial identity to the sequence of amino acid residues 1-208 in Figure 2A, and residues 1-207 in Figure 4A.
  • Mutations in nucleotide sequences constructed for expression of analog IL-4Rs must, of course, preserve the reading frame phase of the coding sequences and preferably will not create complementary regions that could hybridize to produce secondary mRNA structures, such as loops or hairpins, which would adversely affect translation of the receptor mRNA.
  • a mutation site may be predetermined, it is not necessary that the nature of the mutation per se be predetermined. For example, in order to select for optimum characteristics of mutants at a given site, random mutagenesis may be conducted at the target codon and the expressed IL-4R mutants screened for the desired activity.
  • nucleotide sequence which encodes IL-4R will be expressed in the final product, for example, nucleotide substitutions may be made to enhance expression, primarily to avoid secondary structure loops in the transcribed mRNA (see EPA 75,444A, incorporated herein by reference), or to provide codons that are more readily translated by the selected host, e.g., the well-­known E. coli preference codons for E. coli expression.
  • Mutations can be introduced at particular loci by synthesizing oligonucleotides containing a mutant sequence, flanked by restriction sites enabling ligation to fragments of the native sequence. Following ligation, the resulting reconstructed sequence encodes an analog having the desired amino acid insertion, substitution, or deletion.
  • oligonucleotide-directed site-specific mutagenesis procedures can be employed to provide an altered gene having particular codons altered according to the substitution, deletion, or insertion required.
  • Exemplary methods of making the alterations set forth above are disclosed by Walder et al. ( Gene 42 :133, 1986); Bauer et al. ( Gene 37 :73, 1985); Craik ( Bio Techniques , January 1985, 12-19); Smith et al. ( Genetic Engineering: Principles and Methods , Plenum Press, 1981); and U.S. Patent Nos. 4,518,584 and 4,737,462, which are incorporated by reference herein.
  • the present invention provides recombinant expression vectors which include synthetic or cDNA-derived DNA fragments encoding mammalian IL-4R or bioequivalent analogs operably linked to suitable transcriptional or translational regulatory elements derived from mammalian, microbial, viral or insect genes.
  • suitable transcriptional or translational regulatory elements include a transcriptional promoter, an optional operator sequence to control transcription, a sequence encoding suitable mRNA ribosomal binding sites, and sequences which control the termination of transcription and translation, as described in detail below.
  • the ability to replicate in a host usually conferred by an origin of replication, and a selection gene to facilitate recognition of transformants may additionally be incorporated.
  • DNA regions are operably linked when they are functionally related to each other.
  • DNA for a signal peptide is operably linked to DNA for a polypeptide if it is expressed as a precursor which participates in the secretion of the polypeptide; a promoter is operably linked to a coding sequence if it controls the transcription of the sequence; or a ribosome binding site is operably linked to a coding sequence if it is positioned so as to permit translation.
  • operably linked means contiguous and, in the case of secretory leaders, contiguous and in reading frame.
  • DNA sequences encoding mammalian IL-4 receptors which are to be expressed in a microorganism will preferably contain no introns that could prematurely terminate transcription of DNA into mRNA; however, premature termination of transcription may be desirable, for example, where it would result in mutants having advantageous C-terminal truncations, for example, deletion of a transmembrane region to yield a soluble receptor not bound to the cell membrane. Due to code degeneracy, there can be considerable variation in nucleotide sequences encoding the same amino acid sequence; exemplary DNA embodiments are those corresponding to the nucleotide sequences shown in the Figures.
  • inventions include sequences capable of hybridizing to the sequences of the Figures under moderately stringent conditions (50°C, 2 X SSC) and other sequences hybridizing or degenerate to those described above, which encode biologically active IL-4 receptor polypeptides.
  • Transformed host cells are cells which have been transformed or transfected with IL-4R vectors constructed using recombinant DNA techniques.
  • Transformed host cells ordinarily express IL-­4R, but host cells transformed for purposes of cloning or amplifying IL-4R DNA do not need to express IL-4R.
  • Expressed IL-4R will be deposited in the cell membrane or secreted into the culture supernatant, depending on the IL-4R DNA selected.
  • Suitable host cells for expression of mammalian IL-4R include prokaryotes, yeast or higher eukaryotic cells under the control of appropriate promoters. Prokaryotes include gram negative or gram positive organisms, for example E. coli or bacilli.
  • Higher eukaryotic cells include established cell lines of mammalian origin as described below.
  • Cell-free translation systems could also be employed to produce mammalian IL-4R using RNAs derived from the DNA constructs of the present invention.
  • Appropriate cloning and expression vectors for use with bacterial, fungal, yeast, and mammalian cellular hosts are described by Pouwels et al. ( Cloning Vectors: A Laboratory Manual , Elsevier, New York, 1985), the relevant disclosure of which is hereby incorporated by reference.
  • Prokaryotic expression hosts may be used for expression of IL-4Rs that do not require extensive proteolytic and disulfide processing.
  • Prokaryotic expression vectors generally comprise one or more phenotypic selectable markers, for example a gene encoding proteins conferring antibiotic resistance or supplying an autotrophic requirement, and an origin of replication recognized by the host to ensure amplification within the host.
  • Suitable prokaryotic hosts for transformation include E. coli, Bacillus subtilis, Salmonella typhimurium , and various species within the genera Pseudomonas, Streptomyces , and Staphylococcus , although others may also be employed as a matter of choice.
  • Useful expression vectors for bacterial use can comprise a selectable marker and bacterial origin of replication derived from commercially available plasmids comprising genetic elements of the well known cloning vector pBR322 (ATCC 37017).
  • Such commercial vectors include, for example, pKK223-3 (Pharmacia Fine Chemicals, Uppsala, Sweden) and pGEM1 (Promega Biotec, Madison, WI, USA).
  • pBR322 "backbone" sections are combined with an appropriate promoter and the structural sequence to be expressed.
  • E. coli is typically transformed using derivatives of pBR322, a plasmid derived from an E. coli species (Bolivar et al., Gene 2 :95,1977).
  • pBR322 contains genes for ampicillin and tetracycline resistance and thus provides simple means for identifying transformed cells.
  • Promoters commonly used in recombinant microbial expression vectors include the ⁇ -­lactamase (penicillinase) and lactose promoter system (Chang et al., Nature 275:615, 1978; and Goeddel et al., Nature 281:544, 1979), the tryptophan (trp) promoter system (Goeddel et al., Nucl. Acids Res. 8 :4057, 1980; and EPA 36,776) and tac promoter (Maniatis, Molecular Cloning: A Laboratory Manual , Cold Spring Harbor Laboratory, p. 412, 1982).
  • Plasmid vectors available from the American Type Culture Collection which incorporate derivatives of the ⁇ P L promoter include plasmid pHUB2, resident in E. coli strain JMB9 (ATCC 37092) and pPLc28, resident in E coli RR1 (ATCC 53082).
  • Recombinant IL-4R proteins may also be expressed in yeast hosts, preferably from the Saccharomyces genus, such as S. cerevisiae .
  • yeast hosts preferably from the Saccharomyces genus, such as S. cerevisiae .
  • Yeast of other genera, such as Pichia or Kluyveromyces may also be employed.
  • Yeast vectors will generally contain an origin of replication from the 2 ⁇ yeast plasmid or an autonomously replicating sequence (ARS), promoter, DNA encoding IL-­4R, sequences for polyadenylation and transcription termination and a selection gene.
  • yeast vectors will include an origin of replication and selectable marker permitting transformation of both yeast and E. coli , e.g., the ampicillin resistance gene of E. coli and S.
  • cerevisiae trp1 gene which provides a selection marker for a mutant strain of yeast lacking the ability to grow in tryptophan, and a promoter derived from a highly expressed yeast gene to induce transcription of a structural sequence downstream.
  • the presence of the trp1 lesion in the yeast host cell genome then provides an effective environment for detecting transformation by growth in the absence of tryptophan.
  • Suitable promoter sequences in yeast vectors include the promoters for metallothionein, 3-­phosphoglycerate kinase (Hitzeman et al., J. Biol. Chem. 255 :2073, 1980) or other glycolytic enzymes (Hess et al., J. Adv. Enzyme Reg. 7:149, 1968; and Holland et al., Biochem.
  • enolase such as enolase, glyceraldehyde-3-phosphate dehydrogenase, hexokinase, pyruvate decarboxylase, phosphofructokinase, glucose-6-phosphate isomerase, 3-phosphoglycerate mutase, pyruvate kinase, triosephosphate isomerase, phosphoglucose isomerase, and glucokinase.
  • Suitable vectors and promoters for use in yeast expression are further described in Hitzeman, EPA 73,657.
  • Preferred yeast vectors can be assembled using DNA sequences from pBR322 for selection and replication in E. coli (Amp r gene and origin of replication) and yeast DNA sequences including a glucose-repressible ADH2 promoter and ⁇ -factor secretion leader.
  • the ADH2 promoter has been described by Russell et al. ( J. Biol. Chem. 258 :2674, 1982) and Beier et al. ( Nature 300 :724, 1982).
  • the yeast ⁇ -factor leader which directs secretion of heterologous proteins, can be inserted between the promoter and the structural gene to be expressed. See, e.g. , Kurjan et al., Cell 30 :933, 1982; and Bitter et. al., Proc. Natl. Acad. Sci. USA 81 :5330, 1984.
  • the leader sequence may be modified to contain, near its 3′ end, one or more useful restriction sites to facilitate fusion of the leader sequence to foreign genes.
  • Suitable yeast transformation protocols are known to those of skill in the art; an exemplary technique is described by Hinnen et al., Proc. Natl. Acad. Sci. USA 75 :1929, 1978, selecting for Trp+ transformants in a selective medium consisting of 0.67% yeast nitrogen base, 0.5% casamino acids, 2% glucose, 10 ⁇ g/ml adenine and 20 ⁇ g/ml uracil.
  • Host strains transformed by vectors comprising the ADH2 promoter may be grown for expression in a rich medium consisting of 1% yeast extract, 2% peptone, and 1% glucose supplemented with 80 ⁇ g/ml adenine and 80 ⁇ g/ml uracil. Derepression of the ADH2 promoter occurs upon exhaustion of medium glucose. Crude yeast supernatants are harvested by filtration and held at 4°C prior to further purification.
  • Suitable mammalian host cell lines include the COS-7 lines of monkey kidney cells, described by Gluzman ( Cell 23 :175, 1981), and other cell lines capable of expressing an appropriate vector including, for example, L cells, C127, 3T3, Chinese hamster ovary (CHO), HeLa and BHK cell lines.
  • Mammalian expression vectors may comprise nontranscribed elements such as an origin of replication, a suitable promoter and enhancer linked to the gene to be expressed, and other 5′ or 3′ flanking nontranscribed sequences, and 5′ or 3′ nontranslated sequences, such as necessary ribosome binding sites, a polyadenylation site, splice donor and acceptor sites, and transcriptional termination sequences.
  • nontranscribed elements such as an origin of replication, a suitable promoter and enhancer linked to the gene to be expressed, and other 5′ or 3′ flanking nontranscribed sequences, and 5′ or 3′ nontranslated sequences, such as necessary ribosome binding sites, a polyadenylation site, splice donor and acceptor sites, and transcriptional termination sequences.
  • the transcriptional and translational control sequences in expression vectors to be used in transforming vertebrate cells may be provided by viral sources.
  • viral sources for example, commonly used promoters and enhancers are derived from Polyoma, Adenovirus 2, Simian Virus 40 (SV40), and human cytomegalovirus.
  • DNA sequences derived from the SV40 viral genome for example, SV40 origin, early and late promoter, enhancer, splice, and polyadenylation sites may be used to provide the other genetic elements required for expression of a heterologous DNA sequence.
  • the early and late promoters are particularly useful because both are obtained easily from the virus as a fragment which also contains the SV40 viral origin of replication (Fiers et al., Nature 273 :113, 1978).
  • Smaller or larger SV40 fragments may also be used, provided the approximately 250 bp sequence extending from the Hind III site toward the Bgl I site located in the viral origin of replication is included.
  • mammalian genomic IL-4R promoter, control and/or signal sequences may be utilized, provided such control sequences are compatible with the host cell chosen. Additional details regarding the use of a mammalian high expression vectors to produce a recombinant mammalian IL-4 receptor are provided in Example 8 below. Exemplary vectors can be constructed as disclosed by Okayama and Berg ( Mol. Cell. Biol. 3 :280, 1983).
  • a useful system for stable high level expression of mammalian receptor cDNAs in C127 murine mammary epithelial cells can be constructed substantially as described by Cosman et al. ( Mol. Immunol. 23 :935, 1986).
  • pCAV/NOT A particularly preferred eukaryotic vector for expression of IL-4R DNA is disclosed below in Example 2.
  • This vector referred to as pCAV/NOT, was derived from the mammalian high expression vector pDC201 and contains regulatory sequences from SV40, adenovirus-2, and human cytomegalovirus, pCAV/NOT containing a human IL-7 receptor insert has been deposited with the American Type Culture Collection (ATCC) under deposit accession number 68014.
  • ATCC American Type Culture Collection
  • Purified mammalian IL-4 receptors or analogs are prepared by culturing suitable host/vector systems to express the recombinant translation products of the DNAs of the present invention, which are then purified from culture media or cell extracts.
  • supernatants from systems which secrete recombinant protein into culture media can be first concentrated using a commercially available protein concentration filter, for example, an Amicon or Millipore Pellicon ultrafiltration unit. Following the concentration step, the concentrate can be applied to a suitable purification matrix.
  • a suitable affinity matrix can comprise an IL-4 or lectin or antibody molecule bound to a suitable support.
  • an anion exchange resin can be employed, for example, a matrix or substrate having pendant diethylaminoethyl (DEAE) groups.
  • the matrices can be acrylamide, agarose, dextran, cellulose or other types commonly employed in protein purification.
  • a cation exchange step can be employed. Suitable cation exchangers include various insoluble matrices comprising sulfopropyl or carboxymethyl groups. Sulfopropyl groups are preferred.
  • RP-HPLC reversed-phase high performance liquid chromatography
  • Recombinant protein produced in bacterial culture is usually isolated by initial extraction from cell pellets, followed by one or more concentration, salting-out, aqueous ion exchange or size exclusion chromatography steps. Finally, high performance liquid chromatography (HPLC) can be employed for final purification steps.
  • Microbial cells employed in expression of recombinant mammalian IL-4R can be disrupted by any convenient method, including freeze-thaw cycling, sonication, mechanical disruption, or use of cell lysing agents.
  • Fermentation of yeast which express mammalian IL-4R as a secreted protein greatly simplifies purification.
  • Secreted recombinant protein resulting from a large-scale fermentation can be purified by methods analogous to those disclosed by Urdal et al. ( J. Chromatog. 296 :171, 1984).
  • This reference describes two sequential, reversed-phase HPLC steps for purification of recombinant human IL-2 on a preparative HPLC column.
  • Human IL-4R synthesized in recombinant culture is characterized by the presence of non-­human cell components, including proteins, in amounts and of a character which depend upon the purification steps taken to recover human IL-4R from the culture. These components ordinarily will be of yeast, prokaryotic or non-human higher eukaryotic origin and preferably are present in innocuous contaminant quantities, on the order of less than about 1 percent by weight. Further, recombinant cell culture enables the production of IL-4R free of proteins which may be normally associated with IL-4R as it is found in nature in its species of origin, e.g. in cells, cell exudates or body fluids.
  • IL-4R compositions are prepared for administration by mixing IL-4R having the desired degree of purity with physiologically acceptable carriers.
  • Such carriers will be nontoxic to recipients at the dosages and concentrations employed.
  • the preparation of such compositions entails combining the IL-4R with buffers, antioxidants such as ascorbic acid, low molecular weight (less than about 10 residues) polypeptides, proteins, amino acids, carbohydrates including glucose, sucrose or dextrins, chelating agents such as EDTA, glutathione and other stabilizers and excipients.
  • IL-4R compositions may be used to regulate the function of B cells.
  • soluble IL-­4R sIL-4R
  • sIL-4R inhibits the proliferation of B cell cultures induced by IL-4 in the presence of anti-Ig.
  • sIL-4R also inhibits IL-4 induced IgG1 secretion by LPS-activated B cells as determined by isotype specific ELISA and inhibits IL-4 induced Ia expression on murine B cells as determined by EPICS analysis.
  • sIL-­4R also inhibits IL-4 induced IgE synthesis and may accordingly be used to treat IgE-induced immediate hypersensitivity reactions, such as allergic rhinitis (common hay fever), bronchial asthma, atopic dermatitis and gastrointestinal food allergy.
  • IL-4R compositions may also be used to regulate the function of T cells.
  • IL-4R inhibits IL-4 induced proliferation of T cell lines, such as the CTLL T cell line.
  • sIL-4R also inhibits functional activity mediated by endogenously produced IL-4.
  • sIL-4R inhibits the generation of alloreactive cytolytic T lymphocytes (CTL) in secondary mixed leukocyte culture when present in culture concomitantly with a monoclonal antibody against IL-2, such as S4B6.
  • CTL alloreactive cytolytic T lymphocytes
  • Neutralizing agents for both IL-2 and IL-4 are used to inhibit endogenous IL-2 and IL-4, both of which regulate CTL generation and are produced in such cultures.
  • a therapeutically effective quantity of an IL-4 receptor composition is administered to a mammal, preferably a human, in association with a pharmaceutical carrier or diluent.
  • CTLL a murine IL-2 dependent cytotoxic T cell line
  • ATCC TIB 214 The preferred cell line for obtaining high IL-4 receptor selection is CTLL, a murine IL-2 dependent cytotoxic T cell line (ATCC TIB 214).
  • CTLL cells parent cells
  • rmIL-4 fluorescein-­conjugated recombinant murine IL-4
  • rmIL-4 fluorescein-­conjugated recombinant murine IL-4
  • the fluorescein-conjugated IL-4 was prepared by combining aliquots of hyperglycosylated rmIL-4 (300 ⁇ g in 300 ⁇ l of 0.1 M citrate-phosphate buffer, pH 5.5) with 30 ⁇ l of 10 mM sodium m-­periodiate (Sigma), freshly prepared in 0.1 M citrate-phosphate, pH 5.5 and the mixture incubated at 4°C for 30 minutes in the dark. The reaction was quenched with 30 ⁇ l of 0.1 M glycerol and dialyzed for 18 hours at 4°C against 0.1 M citrate-phosphate pH 5.5.
  • CTLL cells (5 x 106) were incubated for 30 min at 37°C in 150 ⁇ l PBS + 1% BSA containing 1 x 10 ⁇ 9 M IL-4-fluorescein under sterile conditions. The mixture was then chilled to 4°C, washed once in a large volume of PBS + 1% BSA and sorted using an EPICS® C flow cytometer (Coulter Instruments). The cells providing the highest level fluorescence signal (top 1.0%) were collected in bulk and the population expanded in liquid cell culture. Alternatively, for single cell cloning, cells exhibiting a fluorescence signal in the top 1.0% were sorted into 96 well tissue culture microtiter plates at 1 cell per well.
  • CTLL-19 exhibited 5 x 105 to 1 x 106 IL-4 receptors per cell.
  • CTLL-19 exhibited 1 x 106 IL-4 receptors per cell and was selected for purification and cloning studies. While the calculated apparent K a values are similar for the two lines, CTLL-19.4 expresses approximately 400-fold more receptors on its surface than does the CTLL parent.
  • CTLL 19.4 cells were maintained in RPMI 1640 containing 10% fetal bovine serum, 50 U/ml penicillin, 50 ⁇ g/ml streptomycin and 10 ng/ml of recombinant human IL-2. Cells were grown to 5 x 105 cells/ml in roller bottles, harvested by centrifugation, washed twice in serum free DMEM and sedimented at 2000 x g for 10 minutes to form a packed pellet (about 2 x 108 cells/ml).
  • the column was then eluted with pH 3.0 glycine HCl buffer containing 0.1% Triton® X-100 to remove the IL-4R and washed subsequently with PBS containing 0.1% Triton® X-100.
  • One ml fractions were collected for the elution and 2 ml fractions collected during the wash.
  • samples were neutralized with 80 ⁇ l of 1 M Hepes, pH 7.4.
  • the presence of receptor in the fractions was detected by the solid phase binding assay as described above, using 125I-labeled IL-4. Aliquots were removed from each fraction for analysis by SDS-PAGE and the remainder frozen at -70°C until use.
  • CTLL 19.4 mIL-4 receptor containing fractions from the mIL-4 affinity column purification were prepared for amino terminal protein sequence analysis by fractionating on an SDS-PAGE gel and then transferred to a PVDF membrane. Prior to running the protein fractions on polyacrylamide gels, it was first necessary to remove residual detergent from the affinity purification process. Fractions containing proteins bound to the mIL-4 affinity column from three preparations were thawed and concentrated individually in a speed vac under vacuum to a final volume of 1 ml.
  • the concentrated fractions were then adjusted to pH 2 by the addition of 50% (v/v) TFA and injected onto a Brownlees RP-300 reversed-phase HPLC column (2.1 x 30 mm) equilibrated with 0.1% (v/v) TFA in H2O at a flow rate of 200 ⁇ l/min running on a Hewlett Packard Model 1090M HPLC. The column was washed with 0.1% TFA in H2O for 20 minutes post injection.
  • the HPLC column containing the bound protein was then developed with a gradient as follows: Time % Acetonitrile in 0.1% TFA 0 0 5 30 15 30 25 70 30 70 35 100 40 0 1 ml fractions were collected every five minutes and analyzed for the presence of protein by SDS PAGE followed by silver staining.
  • amino terminal sequence matched a sequence derived from the clone with position 9 being defined as a Cys.
  • IL-4 receptor cDNA probe In order to screen a library for clones encoding a murine IL-4 receptor, a highly enriched IL-4 receptor cDNA probe was obtained using a subtractive hybridization strategy.
  • Polyadenylated (polyA+) mRNA was isolated from two similar cell lines, the parent cell line CTLL (which expresses approximately 2,000 receptors per cell) and the sorted cell line CTLL 19.4 (which expresses 1 x 106 receptors per cell). The mRNA content of these two cell lines is expected to be identical except for the relative level of IL-4 receptor mRNA.
  • a radiolabeled single-stranded cDNA preparation was then made from the mRNA of the sorted cell line CTLL 19.4 by reverse transcription of polyadenylated mRNA from CTLL 19.4 cells by a procedure similar to that described by Maniatis et al., Molecular Cloning, A Laboratory Manual (Cold Spring Harbor Laboratory, New York, 1982). Briefly, polyA+ mRNA was purified as described by March et al. ( Nature 315 :641-647, 1985) and copied into cDNA by reverse transcriptase using oligo dT as a primer.
  • the aqueous phase was removed to a clean tube and made alkaline again by the addition of NaOH to 0.5 M.
  • the cDNA was then size-fractionated by chromatography on a 6 ml Sephadex® G50 column in 30mM NaOH and 1 mM EDTA to remove small molecular weight contaminants.
  • the resulting size-fractionated CDNA generated from the sorted CTLL 19.4 cells was then hybridized with an excess of mRNA from the unsorted parental CTLL cells by ethanol-precipitating the cDNA from CTLL 19.4 cells with 30 ⁇ g of polyA+ mRNA isolated from unsorted CTLL cells, resuspending in 16 ⁇ l of 0.25 M NaPO4, pH 6.8, 0.2% SDS, 2 mM EDTA and incubating for 20 hours at 68°C.
  • the cDNAS from the sorted CTLL 19.4 cells that are complementary to mRNAs from the unsorted CTLL cells form double stranded cDNA/mRNA hybrids, which can then be separated from the single stranded cDNA based on their different binding affinities on hydroxyapatite.
  • the mixture was diluted with 30 volumes of 0.02 M NaPO4, pH 6.8, bound to hydroxyapatite at room temperature, and single-stranded cDNA was then eluted from the resin with 0.12 M NaPO4, pH 6.8, at 60°C, as described by Sims et al., Nature 312 :541, 1984.
  • Phosphate buffer was then removed by centrifugation over 2 ml Sephadex® G50 spin columns in water.
  • This hybrid subtraction procedure removes a majority of common sequences between CTLL 19.4 and unsorted CTLL cells, and leaves a single-stranded cDNA pool enriched for radiolabeled IL-4 receptor cDNA which can be used to probe a cDNA library (as described below).
  • a cDNA library was constructed from polyadenylated mRNA isolated from CTLL 19.4 cells using standard techniques (Gubler, et al., Gene 25 :263, 1983; Ausubel et al., eds., Current Protocols in Molecular Biology , Vol. 1, 1987). After reverse transcription using oligo dT as primer, the single-­stranded CDNA was rendered double-stranded with DNA polymerase I, blunt-ended with T4 DNA polymerase, methylated with EcoR I methylase to protect EcoR I cleavage sites within the cDNA, and ligated to EcoR I linkers.
  • the resulting constructs were digested with EcoR I to remove all but one copy of the linkers at each end of the cDNA, and ligated to an equimolar concentration of EcoR I cut and dephosphorylated ⁇ ZAP® arms and the resulting ligation mix was packaged in vitro (Gigapack®) according to the manufacturer's instructions.
  • Other suitable methods and reagents for generating cDNA libraries in ⁇ phage vectors are described by Huynh et al., DNA Cloning Techniques: A Practical Approach , IRL Press, Oxford (1984); Meissner et al., Proc. Natl. Acad. Sci. USA 84 :4171 (1987), and Ausubel et al., supra .
  • ⁇ ZAP® is a phage ⁇ cloning vector similar to ⁇ gt11 (U.S. Patent 4,788,135) containing plasmid sequences from pUC19 (Norrander et al., Gene 26 :101, 1987), a polylinker site located in a lacZ gene fragment, and an f1 phage origin of replication permitting recovery of ssDNA when host bacteria are superinfected with f1 helper phage.
  • DNA is excised in the form of a plasmid comprising the foregoing elements, designated Bluescript®.
  • Gigapack® is a sonicated E. coli extract used to package ⁇ phage DNA.
  • ⁇ ZAP®, Bluescript®, and Gigapack® are registered trademarks of Stratagene, San Diego, CA, USA.
  • the radiolabeled hybrid-subtracted cDNA from Example 6 was then used as a probe to screen the cDNA library.
  • the amplified library was plated on BB4 cells at a density of 25,000 plaques on each of 20 150 mm plates and incubated overnight at 37°C. All manipulations of ⁇ ZAP® and excision of the Bluescript® plasmid were as described by Short et al., ( Nucl. Acids Res. 16 :7583, 1988) and Stratagene product literature.
  • Duplicate plaque lift filters were incubated with hybrid-subtracted cDNA probes from Example 6 in hybridization buffer containing 50% formamide, 5 X SSC, 5 X Denhardt's reagent and 10% dextran sulfate at 42°C for 48 hours as described by Wahl et al., Proc. Natl. Acad. Sci. USA76 :3683, 1979. Filters were then washed at 68°C in 0.2 x SSC. Sixteen positive plaques were purified for further analysis.
  • Bluescript® plasmids containing the cDNA inserts were excised from the phage as described by the manufacturer and transformed into E. coli . Plasmid DNA was isolated from individual colonies, digested with EcoR I to release the cDNA inserts and electrophoresed on standard 1% agarose gels.
  • Restriction mapping (shown in Figure 1) and DNA sequencing of the isolated CTLL clones indicated the existence of at least two distinct mRNA populations. Both mRNA types have homologous open reading frames over most of the coding region yet diverge at the 3′ end, thus encoding homologous proteins with different COOH-terminal sequences. DNA sequence from inside the open reading frames of both clones code for protein sequence that is identical to protein sequence derived from sequencing of the purified IL-4 receptor described in more detail in Example 5. Clone 16 and clone 18 were used as the prototypes for these two distinct message types. Clone 16 contains an open reading frame that encodes a 258-amino acid polypeptide which includes amino acids -25 to 233 of Figure 2A.
  • Clone 18 encodes a 230-amino acid polypeptide, the N-terminal 224 amino acids of which are identical to the N-terminus of clone 16 but diverge at the 3′ end with nucleotides CCAAGTAATGAAAATCTG which encode the C-terminal 6 amino acids, Pro-Ser-Asn-Glu-­Asn-Leu, followed by a termination codon TGA. Both clones were expressed in a mammalian expression system, as described in Example 8.
  • pIXY120 is identical to pY ⁇ HuGM (ATCC 53157), except that it contains no cDNA insert and includes a polylinker/multiple cloning site with an Nco I site.
  • This vector includes DNA sequences from the following sources: (1) a large Sph I (nucleotide 562) to EcoR I (nucleotide 4361) fragment excised from plasmid pBR322 (ATCC 37017), including the origin of replication and the ampicillin resistance marker for selection in E. coli ; (2) S.
  • cerevisiae DNA including the TRP-1 marker, 2 ⁇ origin of replication, ADH2 promoter; and (3) DNA encoding an 85 amino acid signal peptide derived from the gene encoding the secreted peptide ⁇ -factor (See Kurjan et al., U.S. Patent 4,546,082).
  • An Asp 718 restriction site was introduced at position 237 in the ⁇ -factor signal peptide to facilitate fusion to heterologous genes. This was achieved by changing the thymidine residue at nucleotide 241 to a cytosine residue by oligonucleotide-directed in vitro mutagenesis as described by Craik, BioTechniques , January 1985, pp.12-19.
  • pBC120 also varies from pY ⁇ HuGM by the presence of a 514 bp DNA fragment derived from the single-stranded phage f1 containing the origin of replication and intergenic region, which has been inserted at the Nru I site in the pBR322 sequence.
  • the presence of an f1 origin of replication permits generation of single-stranded DNA copies of the vector when transformed into appropriate strains of E.
  • pIXY120 is digested with Asp 718 which cleaves near the 3′ end of the ⁇ -factor leader peptide (nucleotide 237) and, for example, BamH I which cleaves in the polylinker.
  • the large vector fragment is then purified and ligated to a DNA fragment encoding the protein to be expressed.
  • a cDNA fragment encoding mIL-4R was excised from the Bluescript® plasmid of Example 8 by digestion with Ppum I and Bgl II to release an 831 bp fragment from the Ppum I site (see FIGURE ) to an Bgl II site located 3′ to the open reading frame containing the mIL-4R sequence minus the first two 5′ codons encoding Ile and Lys.
  • pIXY120 was digested with Asp 718 near the 3′ end of the ⁇ -factor leader and BamH I.
  • the vector fragment was ligated to the Ppum I/ Bgl II hIL-4R cDNA fragment and the following fragment created by annealing a pair of synthetic oligonucleotides to recreate the last 6 amino acids of the ⁇ -factor leader and the first two amino acids of mature mIL-4R.
  • the oligonucleotide also included a change from the nucleotide sequence TGG ATA to CTA GAT which introduces a Xba I restriction site, without altering the encoded amino acid sequence.
  • the foregoing expression vector was then purified and employed to transform a diploid yeast strain of S. cerevisiae (XV2181) by standard techniques, such as those disclosed in EPA 165,654, selecting for tryptophan prototrophs.
  • the resulting transformants were cultured for expression of a secreted mIL-4R protein.
  • Cultures to be assayed for biological activity were grown in 20-50 ml of YPD medium (1% yeast extract, 2% peptone, 1% glucose) at 37°C to a cell density of 1-5 x 108 cells/ml. To separate cells from medium, cells were removed by centrifugation and the medium filtered through a 0.45 ⁇ cellulose acetate filter prior to assay.
  • Supernatants produced by the transformed yeast strain, or crude extracts prepared from disrupted yeast cells transformed the plasmid were assayed to verify expression of a biologically active protein.
  • RNA Polyadenylated RNA was isolated from 7B9 cells, an antigen-dependent helper T cell clone derived from C57BL/6 mice, and used to construct a cDNA library in ⁇ ZAP (Stratagene, San Diego), as described in example 7.
  • ⁇ ZAP Stratagene, San Diego
  • the ⁇ ZAP library was amplified once and a total of 300,000 plaques were screened as described in Example 7, with the exception that the probe was a randomly primed 32P-­labeled 700 bp EcoR I fragment isolated from CTLL 19.4 clone 16. Thirteen clones were isolated and characterized by restriction analysis.
  • Nucleic acid sequence analysis of clone 7B9-2 revealed that it contains a polyadenylated tail, a putative polyadenylation signal, and an open reading frame of 810 amino acids (shown in Fig. 2), the first 258 of which are identical to those encoded by CTLL 19.4 clone 16, including the 25 amino acid putative signal peptide sequence.
  • the 7B9-2 cDNA was subcloned into the eukaryotic expression vector, pCAV/NOT, and the resulting plasmid was transfected into COS-7 cells as described in Example 8. COS-7 transfectants were analyzed as set forth in Example 12.
  • a second cDNA form similar to clone 18 in the CTLL 19.4 library, was isolated from the 7B9 library and subjected to sequence analysis.
  • This cDNA, clone 7B9-4 is 376 bp shorter than clone 7B9-2 at the 5′ end, and lacks the first 47 amino acids encoded by 7B9-2, but encodes the remaining N-terminal amino acids 23-199 (in Fig. 2).
  • clone 7B9-4 (like clone 18 from CTLL 19.4) has a 114 bp insert which changes the amino acid sequence to Pro Ser Asn Glu Asn Leu followed by a termination codon.
  • RNA Polyadenylated RNA was isolated from pooled human peripheral blood lymphocytes (PBL) that were obtained by standard Ficoll purification and were cultured in IL-2 for six days followed by stimulation with PMA and Con-A for eight hours.
  • An oligo dT primed cDNA library was constructed in ⁇ gt10 using techniques described in example 7.
  • a probe was produced by synthesizing an unlabeled RNA transcript of the 7B9-4 cDNA insert using T7 RNA polymerase, followed by 32P-­labeled cDNA synthesis with reverse transcriptase using random primers (Boehringer-Mannheim).
  • This murine single-stranded cDNA probe was used to screen 50,000 plaques from the human cDNA library in 50% formamide/0.4 M NaCl at 42°C, followed by washing in 2 X SSC at 55°C. Three positive plaques were purified, and the EcoR I inserts subcloned into the Bluescript® plasmid vector. Nucleic acid sequencing of a portion of clone PBL-1, a 3.4 kb cDNA, indicated the clone was approximately 67% homologous to the corresponding sequence of the murine IL-4 receptor.
  • clones A5 and B4 These chimeric human IL-4R cDNAS containing PBL-11/PBL-1 and PBL-5/PBL-1 DNA sequences have been termed clones A5 and B4, respectively, as further described in Example 12. These constructs were transfected into COS-7 cells, and assayed for IL-4 binding in a plate binding assay substantially as described in Sims et al. ( Science 241 :585, 1988). Both composite constructs encoded protein which exhibited IL-4 binding activity.
  • the nucleotide sequence and predicted amino acid sequence of the composite A5 construct correspond to the sequence information set forth in Figures 4A-4C, with the exception that a GTC codon encodes the amino acid Val at position 50, instead of Ile. No other clones that were sequenced contained this change.
  • the nucleotide and predicted amino acid sequence of the composite B4 construct also shows that the 25 amino acid leader sequence of PBL-11 is replaced with the sequence Met-Gln-Lys-Asp-Ala-Arg-Arg-Glu-Gly-­Asn.
  • Constructs expressing a soluble form of the human IL-4 receptor were made by excising a 5′-terminal 0.8 kb Sma I- Dra III fragment from PBL-5 and the corresponding 0.8 kb Asp718- Dra III fragment from PBL-­11, of which the Dra III overhangs were blunt-ended with T4 polymerase.
  • the PBL-5 and PBL-11 fragments were separately subcloned into CAV/NOT cut with Sma I or Asp 718 plus Sma I, respectively; these are called soluble hIL-4R-5 and soluble hIL-4R-11, respectively.
  • the final IL-4 receptor amino acid Thr194 codon is followed by the vector-encoding amino acids GlyGlnArgProLeuGlnIleTyrAlaIle before terminating.
  • a second library made from a CD4+/CD8- human T cell clone, T22, (Acres et al., J.Immunol . 138 :2132, 1987) was screened (using duplicate filters) with two different probes synthesized as described above.
  • the first probe was obtained from a 220 bp Pvu II fragment from the 5′ end of clone PBL-1 and the second probe was obtained from a 300 bp Pvu II- EcoR I fragment from the 3′ end of the clone PBL-1.
  • Five additional cDNA clones were identified using these two probes. Two of these clones span the 5′ region containing the 68 bp insert, but neither contain the insert.
  • the third of these clones T22-8 was approximately 3.6 kb in size and contained in an open reading frame of 825 amino acids, including a 25 amino acid leader sequence, a 207 amino acid mature external domain, a 24 amino acid transmembrane region and a 569 amino acid cytoplasmic domain.
  • the sequence of clone T22-8 is set forth in Figures 4A-4C.
  • Figures 5A-5B compare the predicted human IL-4R amino acid sequence with the predicted murine IL-4R sequence and show approximately 53% sequence identity between the two proteins.
  • a third soluble human IL-4 receptor construct was made as follows. cDNA clone T22-8 was cleaved at the DraIII site in the Thr194 codon, and repaired with synthetic oligonucleotides to regenerate Thr194 and Lys195 codons, followed by a termination codon, and a NotI restriction site. A 0.68 kb StyI-NotI restriction fragment of this clone was then blunt-ended at the StyI site and subcloned into a SmaI-NotI digested pCA V/NOT vector. This cDNA expression vector was designated hIL-4R-8.
  • Conditioned medium from COS cells transfected with pCAV-18 or pCAV-7B9-4 (see Example 8) and grown in DMEM containing 3% FBS was harvested three days after transfection. Supernatants were centrifuged at 3,000 cpm for 10 minutes, and frozen until needed. Two hundred ml of conditioned media was loaded onto a column containing 4 ml of muIL-4 Affigel prepared as described above. The column was washed extensively with PBS and IL-4 receptor eluted with 0.1 M glycine, 0.15 M NaCl pH 3.0. Immediately following elution, samples were neutralized with 80 ⁇ l of 1 M Hepes pH 7.4.
  • Samples were tested for their ability to inhibit binding of 125I-muIL-4 to CTLL cells as set forth in Example 1B. Additionally samples were tested for purity by analysis on SDS-PAGE and silver staining as previously described. Alternative methods for testing functional soluble receptor activity or IL-4 binding inhibition include solid-phase binding assays, as described in Example 1C, or other similar cell free assays which may utilize either radio iodinated or colorimetrically developed IL-4 binding, such as RIA or ELISA. The protein analyzed by SDS-PAGE under reducing conditions has a molecular weight of approximately 37,500, and appears approximately 90% pure by silver stain analysis of gels.
  • Purified recombinant soluble murine IL-4 receptor protein may also be tested for its ability to inhibit IL-4 induced 3H-thymidine incorporation in CTLL cells. Pursuant to such methods, soluble IL-4 receptor has been found to block IL-4 stimulated proliferation, but does not affect IL-2 driven mitogenic response.
  • IL-­4 receptor is immunoprecipitated from COS cells transfected with CAV-16, CAV-7B9-2 and CAV-7B9-­4 and labeled with 35S-cysteine and 35S-methionine.
  • Cell associated receptor from CAV-7B9-4 shows molecular weight heterogeneity ranging from 32-39 kDa.
  • Secreted CAV-7B9-4 receptor has molecular weight between 36 and 41 kDa.
  • Cell associated receptor from CAV-16 transfected COS cells is about 40-41 kDa.
  • Receptor characterization studies were also done on COS cells transfected with hIL-4R containing expression plasmids.
  • the two chimeric human IL-4R molecules A5 and B4 (defined in Example 11) were transfected into COS cells and equilibrium binding studies undertaken.
  • the COS monkey cell itself has receptors capable of binding hIL-4; therefore the binding calculations performed on COS cells transfected with and overexpressing hIL-4R cDNAS represent background binding from endogenous monkey IL-4R molecules subtracted from the total binding.
  • COS cells transfected with hIL-4R A5 had 5.3 x 104 hIL-4 binding sites with a calculated K a of 3.48 x 109 M ⁇ 1.
  • the hIL-­4R B4 expressed in COS cells bound 125I-hIL-4 with an affinity of 3.94 x 109 M ⁇ 1 exhibiting 3.2 x 104 receptors per cell.
  • IL-4R expressed in COS cells were also performed. COS cells transfected with clones A5 or B4 in pCAV/NOT were labeled with 35S-cysteine/ methionine and lysed. Human IL-4R was affinity purified from the resulting lysates with hIL-4-coupled Affigel® (as described in Example 4). The hIL-4R A5 and B4 eluted from this affinity support migrated at about 140,000 daltons on SDS-PAGE, agreeing well with previous estimates of hIL-4R molecular weight by cross-linking (Park et al., J. Exp. Med. 166 :476,1987), as well as with estimates of full-length mIL-4R presented here.
  • the truncated protein could be detected in 35S-methionine/cysteine-labeled COS cell transfectants by affinity purification on hIL-4-coupled Affigel® as approximately a 44 kDa protein by SDS-PAGE.
  • Preparations of purified recombinant IL-4 receptor for example, human or murine IL-4 receptor, transfected COS cells expressing high levels of IL-4 receptor or CTLL 19.4 cells are employed to generate monoclonal antibodies against IL-4 receptor using conventional techniques, such as those disclosed in U.S. Patent 4,411,993. Such antibodies are likely to be useful in interfering with IL-4 binding to IL-4 receptors, for example, in ameliorating toxic or other undesired effects of IL-4.
  • IL-4 receptor bearing CTLL 19.4 cells were used as immunogen emulsified in complete Freund's adjuvant and injected in amounts ranging from 10-100 ⁇ l subcutaneously into Lewis rats. Three weeks later, the immunized animals were boosted with additional immunogen emulsified in incomplete Freund's adjuvant and boosted every three weeks thereafter. Serum sample are periodically taken by retro-orbital bleeding or tail-tip excision for testing by dot-blot assay, ELISA (enzyme-linked immunosorbent assay), or inhibition of binding of 125I-IL-4 to extracts of CTLL cells (as described in Example 1). Other assay procedures are also suitable.
  • Hybridoma cell lines generated by this procedure were plated in multiple microtiter plates in a HAT selective medium (hypoxanthine, aminopterin, and thymidine) to inhibit proliferation of non-fused cells, myeloma hybrids, and spleen cell hybrids.
  • Hybridoma clones thus generated were screened for reactivity with IL-4 receptor.
  • Initial screening of hybridoma supernatants utilized an antibody capture and binding of partially purified 125I-­mIL-4 receptor.
  • Two of over 400 hybridomas screened were positive by this method.
  • These two monoclonal antibodies, M1 and M2 were tested by a modified antibody capture to detect blocking antibody. Only M1 was able to inhibit 125I-rmIL-4 binding to intact CTLL cells. Both antibodies are capable of immunoprecipitating native mIL-4R protein from CTLL cells or COS-7 cells transfected with IL-4R clones labelled with 35S-cysteine/methionine.
  • M1 and M2 were then injected into the peritoneal cavities of nude mice to produce ascites containing high concentrations (>1 mg/ml) of anti-IL-4R monoclonal antibody.
  • the resulting monoclonal antibody was purified by ammonium sulfate precipitation followed by gel exclusion chromatography, and/or affinity chromatography based on binding of antibody to Protein G.
  • mice are injected in the footpad with irradiated, allogeneic spleen cells. Irradiated, syngeneic cells are then injected into the contralateral pad. An alloreactive response occurs in the pad receiving the allogeneic cells, the extent of which can be measured by the relative increase in size and weight of the popliteal lymph node draining the site of antigen deposition.
  • mice On day 0 three BALB/C mice were injected in the footpad with irradiated, allogeneic spleen cells from c57BL/6 mice and in the contralateral footpad with irradiated, syngeneic spleen cells.
  • days -1,0 and +1 three mice were injected (intraveneously on days -1 and 0, and subcutaneously on day +1) with 100 ng of purified soluble IL-4R (sIL-4R) in phosphate buffered saline, three mice were injected intraveneously with 1 ⁇ g of sIL-4R, three mice were injected with 2 ⁇ g of sIL-4R and three mice were injected with MSA (control).
  • sIL-4R purified soluble IL-4R
  • the mean difference in weight of the lymph nodes from the sites of allogeneic and syngeneic spleen cells was approximately 2.5 mg for the mice treated with MSA, 1 mg for the mice treated with 100 ng of sIL-4R, and 0.5 mg for mice treated with 1 ⁇ g sIL-4R. No detectable difference in weight of lymph nodes was ascertainable for the mice treated with 2 ⁇ g sIL-4R.
  • IL-­4R significantly (p ⁇ 0.5 in all groups, using a two-tailed T test) suppressed the in vivo lymphoproliferative response in a dose dependent fashion relative to control mice.

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AU4411389A (en) 1990-05-28
DK78491D0 (da) 1991-04-29
US5599905A (en) 1997-02-04
FI912064A0 (fi) 1991-04-29
IE893027L (en) 1990-04-30
DE68928043D1 (de) 1997-06-19
US6391581B1 (en) 2002-05-21
US20030185821A1 (en) 2003-10-02
FI106044B (fi) 2000-11-15
NZ231189A (en) 1991-06-25
US20050118176A1 (en) 2005-06-02
DE68928043T2 (de) 1997-09-11
ATE153068T1 (de) 1997-05-15
JPH02215385A (ja) 1990-08-28
ES2103706T3 (es) 1997-10-01
US5717072A (en) 1998-02-10
DK175583B1 (da) 2004-12-13
EP0367566B1 (de) 1997-05-14
US6716587B2 (en) 2004-04-06
AU643427B2 (en) 1993-11-18
US6548655B1 (en) 2003-04-15
GR3024271T3 (en) 1997-10-31
JP2744821B2 (ja) 1998-04-28
WO1990005183A1 (en) 1990-05-17
US7317090B2 (en) 2008-01-08
US5856296A (en) 1999-01-05
IL91705A (en) 1998-12-27
US5767065A (en) 1998-06-16
US5840869A (en) 1998-11-24
DK78491A (da) 1991-04-30
US20090226472A1 (en) 2009-09-10
IE61013B1 (en) 1994-09-07
IL91705A0 (en) 1990-06-10

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